Frontotemporal dementia (FTD) is a major presenile age-dependent dementia characterized by several clinical features including progressive behavioral changes and language impairments. Pathogenic mutations in progranulin lead to loss of one functional allele and are a major cause of FTD. This commonly observed reduction in functional progranulin indicates haploinsufficiency to be the underlying disease mechanism. There is a critical need to develop treatments to increase progranulin in patients with FTD due to progranulin deficiency. The overall objective of this proposal is to evaluate the modulation of a translational repression mechanism of endogenous progranulin expression with the aim to upregulate progranulin protein levels endogenously and within physiological context and regulation. If our hypothesis is correct, by increasing progranulin levels in human neurons and microglia, it may be possible to restore a healthy control phenotype and delay aspects of disease pathogenesis and neurodegeneration. Our studies will also design and test clinically-relevant antisense oligonucleotides to boost progranulin protein levels. Reduced progranulin levels in the brain have also been linked to the neurodegeneration associated with several diseases, including Alzheimer Disease. Therefore, the development of therapies that increase progranulin expression are likely to be a viable strategy for the prevention or treatment of multiple neurodegenerative diseases.